January 31, 2018

expert reaction to biomarkers for amyloid-beta in Alzheimer’s disease

A new study, published in Nature, investigate plasma biomarkers for predicting amyloid beta deposition in the brain.

Dr Mark Dallas, Lecturer in Cellular and Molecular Neuroscience, University of Reading, said:

“This study looks to detect one hallmark of Alzheimer’s disease, amyloid beta, from blood samples. We know that amyloid beta contributes in part to the death of nerve cells, this loss of nerve cells causes the symptoms of dementia. This report highlights that their test can accurately measure ratios of amyloid beta levels in the blood and that this corresponds to amyloid beta levels in the brain. If the study can be repeated in a larger number of people, this test will give us an insight into changes occurring in the brain, that relate to Alzheimer’s disease, from a routine blood sample. However, using someone’s blood sample as a diagnosis for Alzheimer’s disease is a long way off.”

“The research is of good quality as they have conducted a thorough screen of amyloid peptides in blood and have validated the results in an independent cohort. Not only have they associated plasma biomarkers in blood with PET imaging of brain amyloid, they have also correlated this with amyloid in cerebrospinal fluid measures as well. By using PET imaging of brain amyloid as a proxy measure of pathology, the group has been able to show that blood plasma amyloid correlates with the brain amyloid very well.

“Recently there has been a substantial drive for performing blood-based biomarker research. Amyloid and tau measures in cerebrospinal fluid are considered the ‘best’ biomarker available, and previously, measures of amyloid beta in blood (plasma or serum) have been very inconsistent and rarely correlated with cerebrospinal fluid measures. More recently there has been more research on trying to find novel targets rather than looking at amyloid or tau in blood, as they have previously been so inconsistent.

“One of the major limitations of this study is that that the authors have not considered the source of the amyloid they are measuring in plasma. There are numerous publications that have shown that the major source of amyloid in blood is from platelets. Another major concern is that the authors do not specify what pool of amyloid they are measuring as amyloid has been recently shown to be in three compartments (free, membrane-bound and cell bound). This is what, in my opinion, has produced the inconsistent results from previous studies and why not many groups have been able to reproduce data.

“This study has major implications as it is the first time a group has shown a strong association of blood plasma amyloid with brain and cerebrospinal fluid. However, the approach of obtaining the results are still very complicated. In its current form, the methodology is not practical in a clinical setting. Considering Alzheimer’s disease has a very long pre-clinical phase, a truer test will be how well this test performs in independent, healthy, cognitively normal individuals or even in individuals in the early stages of the disease.”

“We know that damaging changes begin to take place in the brain many years before the symptoms of Alzheimer’s appear, and researchers are now developing new ways to detect the earliest signs of the disease. Searching for reliable markers of disease in blood is a tricky task, as protein levels can be influenced by so many factors that differ between individuals.

“This robust study finds the ratio of slightly different forms of amyloid in the blood ties in well with signs of Alzheimer’s disease on brain scans, a useful step in validating its potential as a diagnostic tool. The study uses data from two countries, which helps overcome differences found in people across locations that is a common problem in blood biomarker studies, and its accuracy in predicting amyloid in the brain is higher than other previous attempts. Given the risk of false positives or negatives from tests like this, further work with more people will need to build on this study to understand how well this approach could predict those who will go on to develop symptoms of Alzheimer’s in the future.”

“A blood marker for Alzheimer’s could prove valuable as a minimally invasive and cost-effective addition to the current diagnostic tests available for the disease. The ability to detect the very earliest stages of Alzheimer’s would not only allow people to receive existing treatments sooner but would also enable new drugs to be trialled in the right people, at the right time.”

Prof. Rob Howard, Professor of Old Age Psychiatry, UCL, said:

“The first thing to say is that this is not a blood test for dementia that people who are worried about their memory and concentration should be asking their doctors about. But this is a potentially very important way of identifying people who have amyloid deposition in their brains, which can only be currently ascertained by an expensive PET scan of the brain. Not everyone with amyloid in their brains will turn out to have dementia and not everyone who does have dementia will be found to have amyloid in their brains, so the results of the blood test will need very careful interpretation and explanation. The potential usefulness of these results will need to be replicated in further independent samples before we know just how significant and useful this is going to be in, for example, the early identification of people with Alzheimer’s disease for inclusion in treatment trials.”

Prof. John Hardy, Professor of Neuroscience, UCL, said:

“This is a very interesting and hopeful study which could have a very positive impact on diagnostic accuracy in the enrolment of patients in Alzheimer clinical trials. As the authors discuss, it may not be useful in assessing clinical efficacy but it may be helpful in making accurate diagnoses.. A very important step.”

“Amyloid plaques are one of the hallmark pathologies of Alzheimer’s disease, which start to accumulate years before dementia symptoms begin. In order to figure out which people are in the very early stages of Alzheimer’s disease, there is a pressing need for robust, non-invasive ways to determine who has this type of pathology in the brain. This study developed a new way to measure amyloid beta and amyloid beta precursor protein levels in blood. The blood measurements of amyloid were 90% accurate in determining which people had amyloid in their brains as measured by a positron-emission tomography (PET).

“This is a robust study in two large groups of people. However, further studies in other cohorts and studies that examine changes in the blood markers over time are needed before this type of blood test will be ready to use in clinical practice. These data are very promising and may be incredibly useful in the future, in particular for choosing which people are suited for clinical trials and for measuring whether amyloid levels are changed by treatments in trials.”

“Blood tests are a hot topic in dementia research; they have the potential to help spot people in the earliest stages of disease, opening up opportunities to test drugs that can slow down or stop dementia from developing. This test alone can’t tell whether someone has Alzheimer’s, or whether they will definitely develop it, but it can predict one of the hallmarks of the disease – amyloid protein build-up in the brain – with reasonable accuracy.

“Here the research team build on their earlier work, using an improved lab technique to further increase the accuracy of their blood test. A blood test is much quicker and cheaper than a brain scan or spinal tap, so this could be a useful tool for researchers to identify people at risk of Alzheimer’s for further investigation. We need to see whether the test works in a larger population, but it has the potential both to speed up clinical trials, and help people in the very early stages of Alzheimer’s to access new treatments if and when they become available.”

“Easily (and cheaply) measured plasma-derived biomarkers that aid diagnosis, stratification or prediction of outcome in individuals suspected of having early signs of disease represent a ‘Holy Grail’ of Alzheimer’s research. The availability of such markers would facilitate early diagnosis, allow early intervention and perhaps provide a means of demonstrating response to intervention. The problem that has stalled progress is that the known markers of Alzheimer pathology, fragments of the amyloid protein that accumulates in the brain, are present in plasma in vanishingly small amounts. Standard assay technologies such as immunoassays have struggled to achieve the necessary sensitivity, although the recent development of ultrasensitive immunoassays (Simoa system) may address this issue.

“In the current issue of Nature, Nakamura and colleagues in Japan and Australia have taken a different approach to address the sensitivity problem. They have used immunoprecipitation from plasma to enrich for amyloid fragments followed by mass spectrometry to quantify (relative to a reference amyloid fragment). They measured three amyloid fragments, APP669-711, Aβ1-42 and Aβ1-40, then computed a composite biomarker from these that, in their original Japanese cohort, was strongly correlated with brain amyloid burden assessed by PET scanning using the PIB ligand. Of note, the ratio of Aβ1-42/Aβ1-40 was equally well correlated. A replication study in an Australian cohort supported the findings, albeit with significant centre effects and much poorer replication when other PET imaging modalities were used to measure amyloid burden. The authors noted the need for further validation and standardisation of methods

“The work is important in that it demonstrates unequivocally that plasma markers can be used to assess disease burden in Alzheimer’s disease and might be useful in diagnosis and in monitoring responses to novel treatments. The test described is technically demanding, requiring immunoprecipitation followed by mass spectrometry, methods that are likely beyond the capabilities of most routine diagnostic labs. There are already automated immunoassay methods for measuring plasma Aβ1-42/Aβ1-40, equally informative in this study. It will be interesting to test whether these simpler methods are equally effective predictors of amyloid burden. Nevertheless, the study clearly shows that PET scanning to assess disease burden, an expensive (~£1000- per scan) and invasive procedure, may not be needed in future either for diagnosis or for monitoring response to treatment. Although further replication and comparison with other available methods is needed urgently, the work shows that, in the near future, (relatively) simple blood tests could replace scans in the management of Alzheimer’s disease.”

* ‘High performance plasma amyloid-β biomarkers for Alzheimer’s disease’ by Nakamura author et al. will be published in Nature at 18:00 UK time on Wednesday 31 January, which is also when the embargo will lift.